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Compositions and methods for detecting and treating ophthalmic disorders

Compositions and methods for detecting and treating ophthalmic disorders description/claims

This application claims priority to pending U.S. Provisional Patent Application Ser. No. 60/974,333, filed Sep. 21, 2007, hereby incorporated by reference in its entirety.

This invention was made with government support under Grant Nos. EY014705 and EY007003 awarded by the National Eye Institute. The government has certain rights in the invention.

The present invention relates to compositions and methods for the detecting, treating, and conducting research on ophthalmic disorders associated with photoreceptor cell death and/or retinal insult. In particular, the present invention provides compositions and methods for increasing IL-6 expression and/or activity (e.g., exogenous IL-6), activating IL-6 receptors (e.g., IL-6R, sIL6-R), activating pathway related compounds (e.g., STAT, FLIP), and/or activating related pathways (e.g., JAK/STAT pathway, TGF-β pathway, Ahr pathway) in the diagnosis, treatment, and conducting research of ophthalmic disorders associated with photoreceptor cell death and/or retinal insult (e.g., retinal detachment).

Next to central retinal artery occlusion and chemical burns to the eye, retinal detachment is one of the most time-critical encountered eye emergencies. Retinal detachment (RD) was first recognized in the early 1700s by de Saint-Yves, but clinical diagnosis remained elusive until Helmholtz invented the ophthalmoscope in 1851.

Retinal detachment refers to separation of the inner layers of the retina from the underlying retinal pigment epithelium (RPE, choroid) and choroid. The choroid is a vascular layer underneath the retina which provides metabolic and nutritional support required by the photoreceptors. The RPE is a monolayer of large branched pigment cells sandwiched between the choroid and the retina, which also participates in metabolic support of the photoreceptors. Separation of the sensory retina from the underlying RPE occurs by the following 3 basic mechanisms: 1) a hole, tear, or break in the neuronal layer allowing fluid from the vitreous cavity to seep in between and separate sensory and RPE layers (ie, rhegmatogenous RD); 2) traction from inflammatory or vascular fibrous membranes on the surface of the retina, which tether to the vitreous; and/or 3) exudation of material into the subretinal space from retinal vessels such as in hypertension, central retinal venous occlusion, vasculitis, or papilledema. RDs may be associated with congenital malformations, metabolic disorders, trauma (including previous ocular surgery), vascular disease, choroidal tumors, high myopia or vitreous disease, or degeneration (including age-related macular degeneration). Of the 3 types of retinal detachment, rhegmatogenous RD is the most common, deriving its name from rhegma, meaning rent or break. Vitreous fluid enters the break and separates the sensory retina from the underlying RPE, resulting in detachment. Exudative or serous detachments occur when subretinal fluid accumulates and causes detachment without any corresponding break in the retina. The etiologic factors are often tumor growth or inflammation. Tractional retinal detachment occurs as a result of adhesions between the vitreous gel and the retina. Centripetal mechanical forces cause the separation of the retina from the RPE without a retinal break. Advanced adhesion may result in the development of a tear or break. The most common causes of tractional RD are proliferative vitreoretinopathy, proliferative diabetic retinopathy, sickle cell disease, advanced retinopathy of prematurity, and penetrating trauma. Vitreoretinal traction increases with age, as the vitreous gel shrinks and collapses over time, frequently causing posterior vitreous detachments in approximately two thirds of persons older than 70 years.

Although 6% of the general population have retinal breaks, most of these are benign atrophic holes, which are without accompanying pathology and do not lead to retinal detachment. Incidence of retinal detachment is 1 in 15,000 population, with a prevalence of 0.3% in the United States. The annual incidence is approximately one in 10,000 or about 1 in 300 over a lifetime (see, e.g., Haimann M H, et al., Arch Ophthalmol February 1982; 100(2): 289-92; herein incorporated by reference in its entirety). Other sources suggest that the age-adjusted incidence of idiopathic retinal detachments is approximately 12.5 cases per 100,000 per year, or about 28,000 cases per year in the United States (see, e.g., Subramanian M L, et al., Int Ophthalmol Clin 2004; 44(4): 103-14; herein incorporated by reference in its entirety). Certain groups have higher prevalence than others. Patients with high myopia (>6 diopters), a condition that is more common in males than in females have a 5% risk; individuals with aphakia (ie, cataract removal without lens implant) have a 2% risk. Cataract extraction complicated by vitreous loss during surgery has an increased detachment rate to 10%. Estimates reveal that 15% of people with retinal detachments in one eye develop detachment in the other eye. Risk of bilateral detachment is increased (25-30%) in patients who have had bilateral cataract extraction.

The development of improved methods for detecting ophthalmic disorders (e.g., RD) and the related progression of such disorders are needed. In addition, new therapeutic treatments are needed for the treatment of ophthalmic disorders involving retinal detachment and are of broad interest to the medical community, as well as to the pharmaceutical and biotech industries. The present invention addresses these issues.

The present invention relates to compositions and methods for the detecting, treating, and conducting research on ophthalmic disorders associated with photoreceptor cell death and/or retinal insult. In particular, the present invention provides compositions and methods for increasing IL-6 expression and/or activity (e.g., exogenous IL-6), activating IL-6 receptors (e.g., IL-6R, sIL6-R), activating pathway related compounds (e.g., STAT, FLIP), and/or activating related pathways (e.g., JAK/STAT pathway, TGF-β pathway, Ahr pathway) in the diagnosis, treatment, and conducting research of ophthalmic disorders associated with photoreceptor cell death and/or retinal insult (e.g., retinal detachment).

Experiments conducted during the development of embodiments for the present invention demonstrated that inhibition of IL-6 accelerates photoreceptor apoptosis in models of RD. As such, in some embodiments, detection of diminished (e.g., reduced, absent) IL-6 expression, IL-6 receptor activity (e.g., IL-6R, sIL6-R), and/or related pathway activity (e.g., FLIP expression, STAT expression) in an affected ocular region (e.g., RPE tissue, retinal tissue) following an ocular insult (e.g., retinal detachment) indicates an increased likelihood of photoreceptor cell death and potential visual impairment. In some embodiments wherein retinal detachment has occurred, detection of diminished (e.g., reduced, absent) IL-6 expression, IL-6 receptor activity (e.g., IL-6R, sIL6-R), and/or related pathway activity (e.g., FLIP expression, STAT expression) in the affected ocular region (e.g., RPE tissue, retinal tissue) indicates a diminishing of the IL-6 protective period following retinal insult and a likelihood of photoreceptor cell death and visual impairment. In addition, experiments conducted during the development of embodiments for the present invention demonstrated that the presence of IL-6 within the subretinal space following an event involving the retina (e.g., retinal trauma resulting in RD) prevented photoreceptor apoptosis in models of RD. As such, in some embodiments wherein retinal detachment has occurred, detection of IL-6 expression, IL-6 receptor activity (e.g., IL-6R, sIL6-R), and/or related pathway activity (e.g., FLIP expression, STAT expression) in the affected ocular region (e.g., RPE tissue, retinal tissue) indicates the likelihood that photoreceptor cell death is being hindered (e.g., prevented, reduced) by the presence of such IL-6 activity. In some embodiments wherein retinal detachment has occurred, detection of IL-6 expression, IL-6 receptor activity (e.g., IL-6R, sIL6-R), and/or related pathway activity (e.g., FLIP expression, STAT expression) in the affected ocular region (e.g., RPE tissue, retinal tissue) indicates the likelihood that the IL-6 protective period is in effect. In some embodiments, detection of a change (e.g., a reduction) in IL-6 expression, IL-6 receptor activity (e.g., IL-6R, sIL6-R), and/or related pathway activity (e.g., FLIP expression, STAT expression) between at least two or more time points in an affected ocular region (e.g., an area of retinal detachment) indicates a diminishing of the IL-6 protective period, and an increased risk for photoreceptor cell death and potential visual impairment.

In certain embodiments, the present invention provides methods for preventing photoreceptor apoptosis within ocular tissue comprising: administering a composition configured to promote IL-6 activity within the ocular tissue. In some embodiments, the ocular tissue comprises photoreceptor cells at risk for undergoing cellular apoptosis. In some embodiments, the ocular tissue comprises retinal tissue and/or retinal pigment epithelial tissue. In some embodiments, the retinal tissue is detached from the retinal pigment epithelial tissue. The methods are not limited to a particular type of subject (e.g., rat, cat, mouse, primate). In some embodiments, the subject is a living human. In some embodiments, the administration comprises direct administration of the composition within the ocular tissue.

In certain embodiments, the present invention provides methods for treating photoreceptor apoptosis in a subject experiencing photoreceptor apoptosis, comprising administering a pharmaceutical composition to the subject, wherein the pharmaceutical composition is configured to inhibit photoreceptor apoptosis within the ocular tissue. In some embodiments, the ocular tissue comprises retinal tissue and/or retinal pigment epithelial tissue. In some embodiments, the retinal tissue is detached from the retinal pigment epithelial tissue. The methods are not limited to a particular type of subject (e.g., rat, cat, mouse, primate). In some embodiments, the subject is a living human. In some embodiments, the subject has been diagnosed with retinal detachment.

In certain embodiments, the present invention provides methods for detecting photoreceptor apoptosis, comprising providing two or more samples from a subject diagnosed with retinal detachment, wherein the two or more samples comprise ocular tissue comprising retinal tissue and/or retinal pigment epithelial tissue, wherein each of the two or more samples are obtained at different time points, quantifying the amount of IL-6 activity in each of the two or more samples, identifying a risk of photoreceptor apoptosis based on the quantifying. In some embodiments, an increase in the quantified IL-6 activity indicates a decreased risk for photoreceptor apoptosis. In some embodiments, a decrease in the quantified IL-6 activity indicates an increased risk for photoreceptor apoptosis. In some embodiments, the two or more samples are two samples. In some embodiments, the second of the two or more samples is obtained more than 5 minutes (e.g., 10 minutes, 20 minutes, 30 minutes, 60 minutes, 2 hours, 5 hours, 12 hours, one day, two days, one week, etc.) after the first sample is obtained.

In certain embodiments, the present invention provides methods for identifying photoreceptor apoptosis inhibitors, comprising providing ocular tissue comprising photoreceptor cells experiencing cellular apoptosis, and a composition comprising an agent; administering the composition to the ocular tissue, quantifying the amount of IL-6 activity and photoreceptor apoptosis in the ocular tissue following administration of the composition to the ocular tissue, wherein the presence or increase of IL-6 activity and decreased photoreceptor apoptosis within the ocular tissue indicates the agent is a photoreceptor apoptosis inhibitor, wherein the absence or decrease of IL-6 activity and photoreceptor apoptosis within the ocular tissue indicates the agent is not a photoreceptor apoptosis inhibitor.

The present invention is not limited to a particular indicator of IL-6 activity. In some embodiments, IL-6 activity includes, but is not limited to, IL-6 activity, JAK/STAT pathway activity, TGF-β pathway activity, Ahr pathway activity, STAT expression and/or activity, FLIP expression and/or activity, endothelin 2 expression and/or activity, ceruloplasmin expression and/or activity, lipocalin 2 expression and/or activity, serpin A3N expression and/or activity, and fibroblast growth factor receptor-1 expression and/or activity.

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• Utility Patent

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